Fidaxomicin: A Novel Macrocyclic Antibiotic for the Treatment of Clostridium difficile Infection

Tonya Crawford, Pharm.D; Emily Huesgen, Pharm.D; Larry Danziger, Pharm.D

Disclosures

Am J Health Syst Pharm. 2012;69(11):933-943. 

In This Article

Pharmacokinetics and Pharmacodynamics

A two-phase Phase I trial was conducted to assess the pharmacokinetics of fidaxomicin in healthy subjects receiving single (phase IA) and multiple (phase IB) oral doses.[29] The first phase was a double-blind, randomized, placebo-controlled, crossover, dose-escalation study that assessed the pharmacokinetics of a single oral dose of fidaxomicin (100, 200, 300, or 450 mg) in 16 healthy adults, followed by a one- to two-week washout period. The Phase IB study design was a multiple-dose, double-blind, randomized, placebo-controlled, dose-escalation study that included 24 healthy adults. Subjects received fidaxomicin (150, 300, or 450 mg daily) or placebo orally for a total of 10 days. Adverse effects reported by subjects were recorded. Plasma, urine, and fecal drug concentrations were analyzed in both phases of this trial.

Plasma concentrations were mostly below the lower limit of quantification (5 ng/mL) after single-dose or multiple-dose oral administration. Four subjects in the multiple-dose study receiving 450 mg daily had a plasma fidaxomicin concentration of 6.13–6.70 ng/mL. No appreciable concentrations of fidaxomicin were detected in the urine (<1% of the drug was excreted in the urine). No accumulation of fidaxomicin was noted in plasma after subjects received the multiple-dose regimen. Based on the limited plasma concentration data available, fidaxomicin was noted to have a half-life of 0.94–2.77 hours.

In Phase IA of the investigation, OP-1118 was isolated to a greater extent (81.57%) than was fidaxomicin (35.01%) in the feces. The peak fecal concentration of fidaxomicin in the 200− and 300-mg groups was 490 μg per gram of feces on day 3. The peak fecal concentration of OP-1118 was 900 μg per gram of feces on day 2. Fecal fidaxomicin concentrations were higher in Phase IB and directly proportional to the administered dose. Serious adverse events were not reported during the course of either phase of the trial.

The pharmacokinetics of fidaxomicin were further analyzed in a Phase II, randomized, open-label study to determine the effective dose for the treatment of mild-to-moderately severe CDI.[45] Forty-eight subjects were randomized to receive fidaxomicin 50, 100, or 200 mg orally every 12 hours for 10 days. Plasma and fecal concentrations of fidaxomicin and OP-1118 were reported. Detectable plasma concentrations were found in 14.3% of subjects in the 100-mg/day treatment group (range, 9.45–12.3 ng/mL), 56.3% of subjects in the 200-mg/day treatment group (range, 5.12–93.7 ng/mL), and 81.35% of subjects in the 400-mg/day treatment group (range, 5.32–84.9 ng/mL). The majority of subjects (93.5%) had plasma fidaxomicin concentrations of <20 ng/mL. Concentrations of OP-1118 were slightly higher, with 39% of subjects having plasma OP-1118 concentrations of >20 ng/mL.

Mean ± S.D. fecal concentrations of fidaxomicin (per gram of feces) on day 10 were 256 ± 136 μg/g (range, 82–558 μg/g) in 100-mg/day recipients, 442 ± 238 μg/g (range, 12–787 μg/g) in 200-mg/day recipients, and 1433 ± 975 μg/g (range, 389–3975 μg/g) in 400-mg/day recipients. Overall, fecal concentrations of OP-1118 on day 10 were similar to fecal concentrations of fidaxomicin, with 393 ± 260 μg/g in 100-mg/day recipients, 430 ± 263 μg/g in 200-mg/day recipients, and 760 ± 373 μg/g in 400-mg/day recipients.

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